DESCRIPTION (applicant's abstract): In the past decade, an extensive body of experimental evidence has been provided to delineate the hypothalamic component of the regulation of daily energy homeostasis and related autonomic and endocrine mechanisms. However, a great part of our current understanding of human physiology and disorders of metabolism is inferred from rodent models, while little is known about the primate hypothalamic circuits that underlie the appropriate coordination of brain functions in the face of changing environment. In particular, it is ill defined whether the same peptidergic circuits known to be involved in the hypothalamic regulation of rodent homeostasis have similar functions in the primate, including human, brain. Our preliminary experiments have revealed both similarities as well as differences between the interaction of particular hypothalamic peptidergic systems in rats and non-human primates. In order to further clarify the significance of rodent models for primate physiology, we propose to determine and compare the interaction of key hypothalamic peptidergic systems in the non-human primate in relation to metabolic regulation. SPECIFIC AIM 1) In monkeys, we will assess and compare the synaptic input of neuropeptide Y (NPY)-containing hypothalamic cells by axons containing hypocretin/orexin (HCRT), melanin concentrating hormone (MCH), pro-opiomelanocortin (POMC), and agouti gene related peptide (AGRP). SPECIFIC AIM 2) To determine the phenotype of hypothalamic neurons expressing c-fos in response to short-term fasting in non-human primates. SPECIFIC AIM 3) To determine the effect of short-term fasting on hypothalamic expression of NPY-, AGRP-, POMC-, MCH-, and HCRT mRNA in the monkey. Our experiments will provide, for the first time, analysis of gene expression, neuronal activation, and qualitative and quantitative synaptology of hypothalamic peptidergic systems related to metabolic processes in individual monkeys. It should be emphasized that the organization of the rhesus monkey hypothalamus is essentially identical to that of the human. Therefore, it can be inferred that the collected data will be especially pertinent to revise our understanding of the neuroendocrine circuits regulating human metabolism. The need to gain further insights into this central mechanism in humans is particularly timely, since disorders related to metabolism are among the leading cause of health problems in the U.S. with the highest financial consequences on the health care system.